CONCISE REVIEW FOR CLINICIANS

Nonceliac Gluten Sensitivity

Maria Vazquez-Roque, MD, MSc, and Amy S. Oxentenko, MD

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Learning Objectives: On completion of this article, you should be able To
(1) define nonceliac gluten sensitivity (NCGS); (2) differentiate NCGS from
celiac disease and wheat allergy; and (3) properly evaluate a patient with sus-
pected NCGS and establish the diagnosis.
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tent of this program but have no relevant financial relationship(s) with industry.
Dr Vazquez-Roque receives research support from Takeda Pharmaceuticals
U.S.A. Dr Oxentenko reports no competing interests.
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Abstract

Nonceliac gluten sensitivity (NCGS) is the clinical term used to describe gastrointestinal (GI) and/or extraintestinal
symptoms associated with gluten ingestion. The prevalence of NCGS is unknown. The condition has clinical
features that overlap with those of celiac disease (CD) and wheat allergy (WA). The pathophysiologic process in
NCGS is thought to be through an innate immune mechanism, whereas CD and WA are autoimmune- and allergen-
mediated, respectively. However, dietary triggers other than gluten, such as the fermentable oligosaccharides, di-
saccharides, monosaccharides, and polyols, have been implicated. Currently, no clinical biomarker is available to
diagnose NCGS. Exclusion of CD and WA is necessary in the evaluation of a patient suspected to have NCGS. The
onset of symptoms in patients with NCGS can occur within hours or days of gluten ingestion. Patients with NCGS
have GI and extraintestinal symptoms that typically disappear when gluten-containing grains are eliminated from
their diets. However, most patients suspected to have NCGS have already initiated a gluten-free diet at the time of an
evaluation. A gluten elimination diet followed by a monitored open challenge of gluten intake to document
recurrence of GI and/or extraintestinal symptoms can sometimes be helpful. If NCGS is strongly suggested, then a
skilled dietitian with experience in counseling on gluten-free diets can provide proper patient education. Additional
research studies are warranted to further our understanding of NCGS, including its pathogenesis and epidemiology,
and to identify a biomarker to facilitate diagnosis and patient selection for proper management.
ª 2015 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2015;90(9):1272-1277

autoimmune nor allergic.1 Celiac disease (CD)

From the Division of Gastro-
enterology and Hepatology,
Mayo Clinic, Jacksonville, FL
Affiliations continued at
the end of this article.
G
luten, a protein found in wheat, is
considered a major food component and wheat allergy (WA) are the best examples
that can trigger gastrointestinal (GI) of autoimmune and allergic gluten-related dis-
symptoms. The gluten-related disorders are clas- orders, respectively. When gluten causes GI
sified by their immunologic pathogenesis: auto- symptoms in the absence of CD or a WA, it is
immune, allergic, and those that are neither considered to be nonceliac gluten sensitivity

1272 Mayo Clin Proc. n September 2015;90(9):1272-1277 n http://dx.doi.org/10.1016/j.mayocp.2015.07.009

www.mayoclinicproceedings.org n ª 2015 Mayo Foundation for Medical Education and Research
NONCELIAC GLUTEN SENSITIVITY
(NCGS), a condition that is neither allergic nor
autoimmune in nature. Nonceliac gluten sensitivity
is the clinical term used to describe GI and/or
extraintestinal symptoms associated with gluten
ingestion that resolve with gluten exclusion
when CD and WA have been properly ruled
out.1-3 Currently, there is no biomarker to diag-
nose NCGS, and the diagnosis is made on clinical
grounds alone. Nonceliac gluten sensitivity is a
food sensitivity thought to trigger an immune-
mediated reaction to gluten-derived antigens,
contrary to CD, which is also an autoimmune
reaction. Nonceliac gluten sensitivity should be
distinguished from a food intolerance because
they are mechanistically different entities. Food
intolerance, with or without malabsorption,
is a nonimmunologic adverse reaction that
occurs when nutrients are not digested prop-
erly or completely because of a lack of neces-
sary digestive enzymes or an excess of a
particular nutrient.4,5 Lactose and fermentable
oligosaccharides, disaccharides, monosaccha-
rides, and polyols (FODMAP) intolerances are
the most common food intolerances.
BACKGROUND
The idea of gluten intake leading to GI symptoms
is not new.6 The concept of gluten sensitivity was
first described in a case series that was published
in 1980.7 Cooper et al7 described 8 patients who
did not appear to have CD on the basis of
biochemical and histologic results. These patients
had chronic diarrhea and abdominal pain,
resolution of symptoms on a gluten-free diet
(GFD), and subsequent recurrence of symptoms
with a gluten challenge. However, there had been
a subsequent paucity of data until 2007, when
Wahnschaffe et al8 described a group of patients
with diarrhea-predominant irritable bowel syn-
drome (IBS) who had clinical improvement on
a GFD in the absence of CD. However, this
response was only significant in patients who
were HLA-DQ2 positive and had IgG antibodies
against tissue transglutaminase and gliadin.
Although not a randomized clinical trial, this
study did explore the relationship between IBS-
like symptoms and gluten, suggested potential
mechanisms for symptom generation, revived
the concept of gluten sensitivity diarrhea, and
enticed further investigations in the field.
Biesiekierski et al9 performed the first ran-
domized, double-blind, placebo-controlled clin-
ical trial in patients with IBS who had a history
Mayo Clin Proc. n September 2015;90(9):1272-1277
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of GI symptoms controlled with a GFD. Patients
were randomized to either a gluten-containing
diet or a placebo diet (continuation of previous
GFD) for 6 weeks, with assessment of GI and
overall symptoms as well as markers of inflam-
mation and intestinal injury. Of the patients in
the gluten-containing diet group, 68% reported
worsening symptoms of pain, bloating, stool con-
sistency, and tiredness within a week compared
with the placebo group. However, no difference
in inflammatory markers or intestinal injury
was observed between the groups. There was
no difference in HLA-DQ2 and HLA-DQ8 status
in any of the study end points. Although this
study was not able to elucidate a mechanism
for symptom development, it suggested gluten
as a dietary trigger for GI symptoms.
A subsequent trial by Vazquez-Roque et al10
randomized patients with IBS to a GFD or a
gluten-containing diet for 30 days, assessing stool
frequency, colonic transit by scintigraphy, and
intestinal permeability. Patients consuming a
gluten-containing diet had increased stool
frequency and increased small-intestine perme-
ability, an effect that was more notable in those
who were HLA-DQ2 positive. No difference in
colonic transit was observed between patients
on a GFD vs a gluten-containing diet. A recent
randomized, double-blind, placebo-controlled,
crossover trial evaluated the effects of low doses
of gluten in patients with suspected NCGS.11
Patients with NCGS had a significant increase
in severity of overall symptoms such as abdom-
inal bloating and pain 1 week after intake of small
amounts of gluten compared with patients who
received placebo.11
The results of these clinical trials suggest that
NCGS does exist as a clinical entity, but there is
still much to learn regarding its pathogenesis
and epidemiology. Nonetheless, considerable
controversy still exists about whether gluten is
the actual dietary trigger causing the GI symp-
toms. Other dietary elements have been sug-
gested as the source of GI distress, such as
other components in wheat products (leading
to the concept of nonceliac wheat sensitivity),
FODMAP, or the amylase-trypsin inhibitors
that are naturally occurring pesticides in
wheat.12,13 In a follow-up study, Biesiekierski
et al12 performed a double-blind crossover trial
in 37 patients with NCGS and IBS (based on
Rome III criteria). Patients were given a 2-week
diet of reduced FODMAP and were then
n http://dx.doi.org/10.1016/j.mayocp.2015.07.009 1273

TABLE 1. Symptoms in Patients With Nonceliac
Gluten Sensitivity
Gastrointestinal Extraintestinal
Bloating “Foggy” mind
Diarrhea Tiredness
Constipation Fatigue
Abdominal pain Joint pain
Nausea Depression
Vomiting Numbness
Anal fissures Loss of balance
Eczema
Anemia
Weight fluctuations
Rash
Headaches
randomized to a high-gluten (16 g/d), low-gluten
(2 g/d of gluten and 14 g/d of whey protein), or
control (16 g/d of whey protein only) diet for 1
week. Gastrointestinal symptoms improved in
all participants with a FODMAP-reduced diet.
However, no GI symptoms were reproduced
on gluten exposure, supporting the theory that
FODMAP and not gluten may be the trigger for
GI symptoms. In addition to FODMAP, recent
data suggest that amylase-trypsin inhibitors,
which are naturally occurring pesticides, may
trigger GI symptoms because they serve as potent
innate immune system stimulants in vitro.13
Controversy regarding NCGS continues, and
further investigations are warranted.
EPIDEMIOLOGY OF NCGS
The prevalence of NCGS and the demographic
characteristics of affected patients are currently
unknown. Establishing the prevalence of
NCGS is challenging given that many patients
initiate a GFD before seeking medical evalua-
tion and there is no biomarker for diagnosis.
Although we do not have accurate estimates
of the prevalence of NCGS, we have data
from the National Health and Nutrition Exam-
ination Survey (NHANES) and from cross-
sectional studies on the prevalence of people
avoiding gluten.14-17 A study of 7762
NHANES participants from 2009 and 2010
found that 0.55% of them were consuming a
GFD.14 At the time of this particular survey,
NCGS was not clearly defined as a clinical en-
tity, and the reasons for gluten avoidance were
not addressed. However, a recent evaluation of
the NHANES participants from 2009-2012
n n
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MAYO CLINIC PROCEEDINGS
distinguished patients with and without CD
who were consuming a GFD. The study found
an overall prevalence of 0.8% of patients
without a CD diagnosis who were consuming
a GFD, irrespective of ethnic background.17
Furthermore, a cross-sectional tertiary referral
center study of patients who had been avoiding
gluten found that 82% of patients started a GFD
before receiving any medical advice, supporting
the fact that the prevalence of NCGS will be
difficult to assess and will be progressively
more challenging given the popularity of
the GFD in the general population.15,16
Double-blind, placebo-controlled challenge
studies in patients with IBS have suggested
that the frequency of NCGS is approximately
30% in that patient population.18 Despite
the availability of some data on the prevalence
of people with or without CD consuming a
GFD, prevalence data on NCGS is still lack-
ing. Further studies are warranted to have a
better estimate of the prevalence of NCGS in
general.
PATHOGENESIS OF NCGS
The pathophysiology of NCGS and the devel-
opment of GI and extraintestinal symptoms in
the absence of CD are not clear. A study by
Sapone et al19 found that the pathogenesis of
CD and NCGS were different. They suggested
that NCGS triggers an innate immune response
as illustrated by increased innate markers such
as toll-like receptors, which is different from
the adaptive response seen in CD. It is important
to note that the innate immune response is a
first line of defense that depends on cytokines
and does not confer long-lasting immunity,
contrary to the adaptive response seen in CD
that relies on antibody production and does
confer immunologic memory for future anti-
genic exposure. However, further evidence
supporting an innate immune response in
NCGS is lacking, and further investigation is
warranted.
Much of the controversy surrounding NCGS
relates to whether it is truly a clinical entity sepa-
rate from CD or IBS or whether it represents CD
in its earliest clinical form and whether gluten is
the actual trigger for GI symptoms rather than
another dietary trigger found in wheat. Some
experts suggest that NCGS is a subgroup of IBS
because of their overlapping symptoms, given
that prior studies have found that a subset of
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NONCELIAC GLUTEN SENSITIVITY
TABLE 2. Comparison of Gluten-Related Disorders
Variable Celiac disease
Symptom onset Days to weeks
Pathogenesis Autoimmunity and innate immunity
HLA HLA-DQ2/HLA-DQ8 restricted
Autoantibodies Almost always present
Enteropathya Almost always present
Features Intestinal and extraintestinal
Complications Comorbidities, long-term complications
a
Enteropathy is defined histologically by villous atrophy and crypt hyperplasia.
Adapted from Gastroenterology,5 with permission from Elsevier.
patients with IBS have a symptomatic response to
a GFD.10,12 Nonceliac gluten sensitivity may be
considered a different entity from IBS because
the potential underlying mechanism leading to
GI symptoms is different. Moreover, certain
studies have suggested that FODMAP may be
the trigger for GI symptoms rather than
gluten.12,20 However, the potential pathogenesis
for symptom generation with gluten and
FODMAP seems to be different. Gluten, as it
relates to NCGS, is regarded as a food sensitivity,
whereas a reaction to FODMAP-containing foods
is considered a food intolerance. Food sensitiv-
ities are immune-mediated reactions to nutrients
that elicit GI and extraintestinal symptoms that
are not shared with food intolerances.4 Studies
have found that on gluten ingestion, some
patients have increased intestinal permeability
with reduced expression of tight junction
proteins.10 A recent study used confocal laser
endomicroscopy in 36 patients with IBS-like
symptoms and performed food provocation
studies in the duodenum through the endoscope,
evaluating intervillous space, epithelial bre-
aks, and intraepithelial lymphocyte density
compared with subsequent histologic exami-
nation findings.21 Of the 36 patients, 22 had
positive confocal laser endomicroscopic find-
ings, with 13 patients reacting to wheat and more
than 50% with GI symptom improvement after
exclusion of the food antigen over a 4-week
period. These studies suggest that there is stimu-
lation of the innate immune system with food
triggers, supporting a potential pathogenesis of
NCGS and suggesting that it may be a different
entity from IBS.
The pathogenesis of NCGS is not fully under-
stood, and whether gluten itself may be the cause
of symptom development or a different trigger
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Nonceliac gluten sensitivity Wheat allergy
Hours to days Minutes to hours
Innate immunity? Allergic immunity
Not HLA-DQ2/HLA-DQ8 restricted Not HLA-DQ2/HLA-DQ8 restricted
Always absent Always absent
Always absent Always absent
Intestinal and extraintestinal Intestinal and extraintestinal
Comorbidities, long-term complications? No comorbidities, anaphylaxis
such as foods high in FODMAP or the amylase-
trypsin inhibitors found in wheat may be the
causative factors remains controversial. Further
studies are warranted to further elucidate this as-
sociation and the pathogenesis of gluten-induced
GI symptoms.
CLINICAL PRESENTATION OF NCGS
The onset of symptoms in patients with
NCGS can occur within hours or days of
gluten ingestion. The symptoms of NCGS
include GI symptoms as well as extraintesti-
nal features. Commonly reported GI symp-
toms include abdominal pain, bloating,
diarrhea, and constipation.22-24 Extraintesti-
nal features of NCGS include “foggy” mind,
fatigue, headache, leg or arm numbness,
depression, joint pain, anemia, and rash,
among others.22,23 Table 1 summarizes the
GI and extraintestinal symptoms reported in
patients with NCGS. These symptoms disap-
pear when gluten-containing grains are elimi-
nated from the diet. It is difficult to
distinguish NCGS and CD on the basis of
symptoms alone because there is consider-
able overlap between the 2 conditions, and
further investigations are necessary to make
the appropriate diagnosis.
In the clinical evaluation of a patient sus-
pected to have NCGS, it is important to rule
out CD and WA. Table 2 summarizes the
key differences between these clinical disor-
ders and NCGS. The initial evaluation should
include tissue transglutaminase IgA serology
(with or without measurement of the IgA
level) while the patient is consuming a
gluten-containing diet and measurement of
the serum wheat IgE level to exclude CD
and WA, respectively.25,26 If the patient is
1275

consuming a GFD at the time of the evalua-
tion, then performing HLA testing to assess
for the presence of DQ2 and DQ8 permissive
gene types is necessary. If HLA-DQ2 and
HLA-DQ8 are both absent, then CD can be
excluded. However, if either permissive
HLA type is found and the patient is
consuming a GFD, then a minimum 2-week
gluten challenge can be pursued and repeated
CD testing can be performed thereafter.26
Upper endoscopy with small-bowel biopsies
may be necessary to differentiate NCGS,
CD, and latent CD. If after a 2-week gluten
challenge a patient has positive results on
CD serologic examination and normal
small-bowel biopsy findings, they likely
have latent CD and need to be counseled
and treated accordingly. In NCGS, there will
be no villous atrophy or crypt hyperplasia
as seen in CD. The presence of isolated intra-
epithelial lymphocytosis on duodenal biopsy
specimens is not specific for CD, and other
conditions need to be considered if that is
the only histologic feature noted.27 To facili-
tate the diagnosis of NCGS, a patient can
undergo an elimination diet followed by a
monitored open challenge of gluten intake
to document if there is recurrence of GI and/or
extraintestinal symptoms. However, an open
food challenge is not without limitations. When
measuring subjective symptoms in an open
food challenge, there are false-positive results
with a high nocebo effect. Once NCGS is sus-
pected, a skilled dietitian with experience in
counseling on GFDs can ensure proper patient
education and avoid long-term restrictive diets.
The most effective duration of a GFD in a patient
with NCGS is not well established. The natural
history of NCGS is not clear, and the possible
benefits of a rechallenge with gluten within
months or years is yet to be determined.
CONCLUSION
Nonceliac gluten sensitivity is a clinical entity
with GI and extraintestinal features that requires
exclusion of CD and WA for proper diagnosis
because of the overlapping features of these
disorders. Current pathogenic and diagnostic
challenges in NCGS preclude complete un-
derstanding of this clinical entity in practice.
Future investigations are needed to further
our understanding of its pathogenesis and
to identify a biomarker to facilitate diagnosis.
n n
1276 Mayo Clin Proc. September 2015;90(9):1272-1277
MAYO CLINIC PROCEEDINGS
Better understanding of these features of
NCGS will facilitate treatment selection and
long-term therapeutic goals.
Abbreviations and Acronyms: CD = celiac disease;
FODMAP = fermentable oligosaccharides, disaccharides,
monosaccharides, and polyols; GFD = gluten-free diet; GI =
gastrointestinal; IBS = irritable bowel symdrome; NCGS =
nonceliac gluten sensitivity; NHANES = National Health and
Nutrition Examination Survey; WA = wheat allergy
Affiliations (Continued from the first page of this
article.): (M.V.-R.); and Division of Gastroenterology,
Mayo Clinic, Rochester, MN (A.S.O.).
Potential Competing Interests: Dr Vazquez-Roque re-
ceives research support from Takeda Pharmaceuticals
U.S.A. Dr Oxentenko reports no competing interests.
Correspondence: Address to Maria Vazquez-Roque, MD,
MSc, Division of Gastroenterology and Hepatology, Mayo
Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224.
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